- BioRxiv Biochemistry
- BioRxiv Bioinformatics
- BioRxiv Biophysics
- BioRxiv Cancer Biology
- BioRxiv Pharmacology and Toxicology
- BioRxiv Systems Biology
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- by Montano-Gutierrez, L. F., Mueller, S., Kutschat, A. P., Seruggia, D., Halbritter, F.A prime goal of regenerative medicine is to replace dysfunctional cells in the body. To design protocols for producing target cells in the laboratory, one may need to consider exponentially large combinations of culture components. Here, we investigated the potential of iteratively approximating the target phenotype by quantifying the distance between chromatin profiles (ATAC-seq) of differentiating cells in vitro and their in-vivo counterparts. We tested this approach on the well-studied generation of erythroblasts from haematopoietic stem cells, evaluating a fixed […]
- by ROTHAN, H., Mostafa, A., Bayoumi, M., Ye, C., Barre, R., Allue Guardia, A., Nogales, A., Torrelles, J. B., Martinez-Sobrido, L. B.Influenza A virus (IAV) pandemics continue to pose serious global health threats, particularly to immunocompromised individuals, children, and the elderly. IAV infections trigger inflammation and tissue damage, promoting lung fibrosis. Unraveling these mechanisms is key to preventing and treating viral-induced pulmonary fibrosis and its lasting impact on respiratory health. Despite available antivirals and vaccines, there is a lack of FDA-approved therapeutics for severe or prolonged IAV pathogenesis. We modeled infection with a recombinant highly pathogenic human A/Texas/37/2024 H5N1 (rHPh-TX H5N1) […]
- by Kikuta, K., Lee, E., Menezes, T., Fung, H. F., Amorin, A., Agrawal, A., Roth, T., Porteus, M.Despite its therapeutic potential and unique immunological properties, the immune composition of umbilical cord blood lacks consistent and comprehensive characterizations. Human umbilical cord blood (UCB) is often discarded after delivery and is difficult to obtain for research purposes. Furthermore, most research on UCB is focused on properties of CD34+ hematopoietic stem cells for transplantation. The Binns Program for Cord Blood Research at Stanford University has the unique advantage of regular collection and isolation of mononuclear cells (MNC) from UCB donors. […]
- by Chira, N., Swatler, J., Manousopoulou, A., Rumney, R. M. H., Hajto, J., Oksiejuk, A., Garay Baquero, D. J., Rog, J., White, C. H., Hinz, S., Alnassar, N., Young, C., Arkle, S., Korostynski, M., Kozlowska, E., Garbis, S. D., Gorecki, D. C.Mutations in the DMD gene, encoding dystrophins, cause progressive muscle degeneration with severe sterile inflammation. While macrophages predominate amongst muscle-infiltrating cells, being central to both damage and regeneration, they were not known to express dystrophin. Yet, we recently demonstrated Dp71 dystrophin expression correlating with tumour infiltrating macrophages. Here we report physiological, developmentally regulated expression of Dp71 in human and mouse hematopoietic stem cells, which decreases with cell maturation into bone marrow macrophages (BMM). Proteomics with molecular and functional analyses in […]
- by Liu, X.-M., Pribiag, H., Misri, D., Kim, K., Mandell, K. P., Song, B. J., Graykowski, D., Seidel, O., Hartley, N. D., Herrera, M., Xu, H. J., Tegtmeyer, M., Zhang, Y.-L., Cui, L., Clark, N., Huang, W.-C., Adeleye, J., Dennis, C., Dailey, L., Deik, A., Inunciaga, L., Mashin, E., Simmons, S. K., Pan, J. Q., Nehme, R., Keshishian, H., Carr, S. A., Fu, Z., Levin, J. Z., Clish, C. B., Sheng, M.A-Kinase Anchoring Protein 11 (AKAP11) is a shared genetic risk factor for schizophrenia and bipolar disorder, yet its role in the brain remains poorly understood. Through multi-omic analysis of Akap11 mutant mouse brains and cultured astrocytes, we identified significant transcriptomic, proteomic, and metabolomic alterations. Key findings include the upregulation of cholesterol and fatty acid metabolic pathways, accumulation of lipid species such as cholesteryl esters, triacylglycerols, ceramides, and glycerophospholipids, and elevated levels of 3',5'-cyclic AMP and protein kinase A (PKA) signaling. […]
- by Tao, S., Feng, Y., Yang, Y., Wu, M., Zheng, J.Synthetic lethality (SL) offers a promising approach for targeted cancer therapies. Current SL prediction models heavily rely on extensive labeled data for specific cell lines to accurately identify SL pairs. However, a major limitation is the scarcity of SL labels across most cell lines, which makes it challenging to predict SL pairs for target cell lines with limited or even no available labels in real-world scenarios. Furthermore, gene interactions could be opposite between training and test cell lines, i.e. SL […]
- by Falconi, J., Rodriguez-Vazquez, M., Strobel, K., Jahannault-Talignani, C., Heron-Milhavet, L., Lassus, P., Geminard, C., Djiane, A.In animals, tumour development triggers systemic effects, impacting the physiology of distant organs. In Drosophila larvae, wing disc neoplastic tumours result in developmental delay and organ wasting reminiscent of cachexia. This paraneoplastic syndrome affects many organs, but its effects on the intestine, a key organ in the regulation of nutrient and energy homeostasis, remain understudied. We describe here that neoplastic tumours also affect the development of the larval midgut, leading to altered cell type numbers, with a depletion of the […]
- by Tiper, Y., Ni, J., Krawetz, R., Gilbert, P. M.Insulin resistance in skeletal muscle is a hallmark of type 2 diabetes mellitus (T2D). While two-dimensional myotube cultures offer a controlled environment for studying T2D-related metabolic dysfunction, insulin-dependent glucose transporter type 4 (GLUT4) levels are limited and insulin-independent glucose transporter type 1 (GLUT1) expression dominates; reducing physiological relevance. Three-dimensional skeletal muscle microtissue cultures offer a promising alternative, and unlike 2D myotubes, are amenable to repeated contractile stimulation. However, microtissue GLUT1 and GLUT4 glucose transporter profiles remain under-characterized, particularly under physiological […]
- by Feldmann, J. W., Kays, M., McGinnis, F., Herron, E., Sati, N., Woods, C., Coulibaly, A.Janus Kinase 2 (JAK2) has been linked to various neutrophil functions, but the intracellular mechanisms underlying its modulation are unknown. Neutrophils are essential cells for host defense. Neutrophil effector functions include migration, reactive oxygen species (ROS) production, degranulation, and neutrophil extracellular trap (NET) formation. The goal of this study was to elucidate the signaling mechanism through which JAK2 modulates neutrophil function and the effect of aging on this pathway. We hypothesized that JAK2-mediated modulation changes the molecular mechanisms associated with […]
- by Jirsova, D., Licknack, T., Poh, Y.-P., Qiu, Y., Quan, N., Karr, T., Chou, T.-F., Lynch, M., Wideman, J. G.Ciliates are unicellular heterotrophic eukaryotes, most of which consume other microbes as prey. They exhibit nuclear dimorphism which requires reconstruction of a transcriptionally active macronucleus from the germline micronucleus after sexual recombination. This complex genomic structure has prevented the development of highly tractable genetic models leaving much of ciliate cell biology unexplored. To complicate matters further, some ciliates tend to accumulate many gene duplicates either singly or via whole genome duplications. Thus, extensive insight into the cell biology of ciliates […]
- by Srivastava, N., Calabrese, L., Plancke, C., Rollin, R., Venkova, L., Havas, K., Cosentino Lagomarsino, M., Piel, M.The concentration of macromolecules, especially proteins, is vital for cellular function and is influenced not only by synthesis and degradation but also by the total cell volume. While we understand various growth regulation mechanisms, the coupling of dry mass and volume in growing mammalian cells remains unclear. Here we show that two independent mechanisms acting in single cells, one regulating volume through biophysical modulation and the other controlling protein biosynthesis, work together to maintain macromolecular dry mass density and restore […]
- Heterogeneous therapy-resistant cancer cells have distinct and exploitable drug sensitivity profilesby Busch, G. T., Boe, R. H., Li, J., Gruener, R. F., Arnett, M. J., Ravindran, P. T., Herlyn, M., Huang, R. S., Raj, A.Resistance to targeted therapies is a significant clinical problem, but eliminating resistant cancer cells has proven difficult. One potential reason for this difficulty is heterogeneity in the resistant population: even genetically homogeneous cancer cell populations can give rise to a variety of resistant subtypes, each potentially with their own specific second-line drug vulnerabilities. Using high-throughput drug screening of genetically-identical resistant clones with varying transcriptomes and morphologies, we show that each clone had a distinct drug sensitivity profile. These results admitted […]
- by Haase, M. A. B., Lazar-Stefanita, L., Baudry, L., Wudzinska, A., Zhou, X., Rokas, A., Hittinger, C. T., Musacchio, A., Boeke, J. D.The evolutionary origins of the genetic point centromere in the brewer's yeast Saccharomyces cerevisiae, a member of the order Saccharomycetales, are still unknown. Competing hypotheses suggest that the point centromere tripartite genetic centromere DNA elements (CDEs) either evolved from ancestral epigenetic centromeres by descent with modification or were gained through horizontal transfer from selfish DNA plasmids. Here, we identified centromeres in the sister order Saccharomycodales and termed them "proto-point centromeres" due to sequence features that bridge the evolutionary gap between […]
- by Hariharan, M., Patel, S., Song, H., Rehman, A., Barragan, C., Bartlett, A., Castanon, R., Nery, J., Rothenberg, V., Chen, H., Tian, W., Ding, W., Wang, W., McAdam, J., Graham, Z., Lavin, K., Bamman, M., Broderick, T., Ecker, J.Exercise and diet are direct physical contributors to human health, wellness, resilience, and performance [1-5]. Endurance and resistance training are known to improve healthspan through various biological processes such as mitochondrial function [6-8], telomere maintenance [9], and inflammaging [10]. Although several training prescriptions have been defined with specific merits [1,10-20], the long-term effects of these in terms of their molecular alterations have not yet been well explored. In this study, we focus on two combined endurance and resistance training programs: […]
- by He, L., Joshi, P., Ioannidis, A., Kathiravan, A., Saki, M., Pajonk, F.Background: The lack of a molecular target in triple-negative breast cancer (TNBC) makes it one of the most challenging breast cancers to treat. Current standard-of-care primarily relies on cytotoxic chemotherapy and radiotherapy, but long-term outcomes remain poor largely due to early relapse, therapy resistance, and high incidents of metastases. More recently, dopamine signaling has emerged as a novel area of interest in cancer biology. Dopamine receptors have been implicated in tumor progression, maintenance of cancer stem-like cells, and therapy resistance […]
- by Kapoor, R., Kim, H., Garlick, E., Lima, M. A. d. R. B. F., Ruhwedel, T., Moebius, W., Wolf, F., Moser, T.For us to hear, the cochlea encodes sounds into neural signals at synapses of inner hair cells (IHCs) and the auditory nerve with remarkable fidelity. To achieve the high rates of temporally precise synaptic transmission over long periods of time, IHCs employ sophisticated ribbon-type active zones (AZ). In order for us to understand synaptic sound encoding, we need to decipher the underpinning molecular topography of these synapse which had remained challenging due to technological limitations. Here we applied 3-dimensional minimal […]
- by Zhao, T., Pelegrina-Hidalgo, N., Edwards, D. C., Bak, K. M., Karmakar, U., Fernando, A. J., Vendrell, M., Rossi, A. G., Kunath, T., Cockroft, S. L., Saleeb, R. S., Horrocks, M. H.Extracellular vesicles (EVs) are small, membrane-bound particles released by cells into the extracellular environment. They play a pivotal role in cell communication and have recently gained prominence as biomarkers. However, their low abundance and high heterogeneity challenges their accurate characterization using conventional approaches. To enable the specific detection of individual EVs, we coupled EV-specific antibodies labeled with two different fluorophores with fast-flow microfluidics and single-molecule confocal microscopy. This allowed us to determine the concentration of EVs down to femtomolar levels […]
- by Xie, K., Sahlas, E., Ngo, A., Chen, J., Arafat, T., Royer, J., Zhou, Y., Rodriguez-Cruces, R., Dascal, A., Caldairou, B., Fadaie, F., Barnett, A., Audrain, S., Lariviere, S., Caciagli, L., Pana, R., Weil, A. G., Grova, C., Frauscher, B., Schrader, D. V., Zhang, Z., Concha, L., Bernasconi, A., Bernasconi, N., Bernhardt, B. C.Temporal lobe epilepsy (TLE) presents with substantial inter-patient variability in clinical and neuroimaging manifestations. This multicenter study examined inter-individual differences in spatial patterns of intrinsic brain function in TLE using normative modeling at multiple spatial scales and evaluated the effectiveness of individual functional deviations for clinical diagnosis and postsurgical outcome prediction. We analyzed multimodal MRI data on 298 healthy controls, 282 TLE patients, and 45 disease controls with extratemporal epilepsy. Cortical function was profiled at local, regional, and global scales […]
- by Tamilkumar, V. N., Purushothama, H., Ladher, R. K.Epithelial fusion is a fundamental morphogenetic process critical for the closure and compartmentalisation of developing organs. While widely studied in systems such as neural tube and palatal closure, the cellular transitions that enable fusion remain poorly understood. Here, we investigate epithelial fusion during chick otic vesicle (OV) closure and identify a transient population of cells at the epithelial interface that mediate this process. These otic edge (OE) cells exhibit distinct morphology, reduced apicobasal polarity, and dynamic junctional remodelling, including altered […]
- by Rust, N. C., Yang, Y.-P. C., Hacker, C. M., Stuphorn, V.Understanding how the brain reflects and shapes mood requires resolving the disconnect between behavioral measures of mood that can only be made in humans (typically based on subjective reports of happiness) and detailed measures of brain activity only available in animals. To achieve this, we developed a universal mood model to predict behavioral fluctuations in human subjective happiness as individuals experienced wins and losses during a gambling task. Next, we investigated how this operationalization of mood was reflected in the […]